Group A Streptococcus (GAS) causes benign to life-threatening infections that can also trigger autoimmune diseases, including acute rheumatic fever. A detailed understanding of the mechanisms by which GAS avoids killing by the host immune system to colonize the host and identifying cross-reactive GAS antigens is critical for a successful combating of streptococcal infections. Thus, the long-term objective is to determine that the streptococcal collagen-like protein 1 (Scl1) is an indispensable accessory protein, which is instrumental to the pathogenesis of rheumatogenic M6-type GAS that leads to induction of anti-collagen autoimmunity. This application is focused on the role of Scl1 in immune evasion as an initial step in pathogenesis. The objectives of this application are to define the mechanism of factor H binding to native Scl1 on GAS cells, and to determine the importance of Scl1-factor H interaction in GAS survival in human blood, and in the pathogenesis in mice. We propose two specific aims: (1) To characterize the interactions of native Scl1 protein with normal and abnormal factor H, and to define the role of factor H binding by the Scl1 protein in GAS escape from complement-mediated destruction;and (2) To demonstrate that Scl1-factor H interaction during mouse infection augments disease progression. A combination of genetic dissection, in vitro binding and functional assays, and in vivo studies using normal and factor H-depleted mice will be used to accomplish these goals. We hypothesize that Scl1 is the major factor H-binding molecule that is necessary for the full protection of the M6-type GAS from complement-mediated opsonization and phagocytosis in vitro. In addition, we also propose that factor H binding by Scl1 in vivo enhances GAS survival and infection dissemination in mice. The proposed study is expected to demonstrate that Scl1 is major determinant of GAS immune evasion. Relevance to public health: The proposed investigations will fill a critical gap in our understanding of the mechanisms of GAS immune evasion. Targeting these mechanisms could be an effective strategy against GAS infections. PUBLIC HEALTH RELEVANCE: Group A streptococcal (GAS) infections are responsible for significant human morbidity and mortality worldwide but there are no effective strategies for global intervention. GAS cells contain surface proteins that are important for pathogenesis. The objective of our research is to characterize the role of a cell surface protein, called Scl1, in GAS immune evasion. Our studies will contribute towards understanding some of the mechanisms by which these bacteria survive human immune responses and produce disease.